This invention relates generally to microfilters useful, for example, for separating plasma from whole blood. Analyzable quantities of plasma, i.e., from about 1 picoliter to a few hundred nanoliters, can be separated from one drop of whole blood within a few seconds by microfilters of this invention.
Many blood tests must be performed on plasma without cellular matter present. In the standard laboratory protocol, pure plasma is obtained through centrifugation. In order to produce a miniaturized blood sensor, a method to separate plasma other than centrifugation is needed.
Chemical analysis of biological samples is constrained by sample size. Withdrawing a few milliliters of blood from an adult may have little effect, but repeating this procedure every hour or even withdrawing this amount once from an infant can significantly alter the health of the subject. For these reasons, a miniaturized blood analysis system would be useful. Furthermore, while many sophisticated tests that have great importance for critical care can be performed in major hospital laboratories, a substantial impact could be made on the practice of emergency medicine if some key tests could be performed on the patient at the site of injury.
Microfabricated fluid filters exist in the literature; however, these lack the advantages of the microfilter of the present invention.
Kittisland, G., and Stemme, G. (1990), xe2x80x9cA Sub-micron Particle Filter in Silicon,xe2x80x9d Sensors and Actuators, A21-A23:904-907; and Stemme, G. and Kittisland, G. (1988), xe2x80x9cNew fluid filter structure in silicon fabricated using a self-aligning technique,xe2x80x9d Appl. Phys. Lett. 53:1566-1568, describe microfilters fabricated using a silicon wafer and capable of filtering out particles down to 50 nm. This filter design cannot be etched into the surface of a silicon wafer. Further, although these filters seem to a perform well for gases, surface tension causes problems when filtering liquids. Gravesen, P., et al. (1993), xe2x80x9cMicrofluidicsxe2x80x94a review,xe2x80x9d J. Micromech. Microeng. 3:168-182.
Wilding, P., et al. (1994), xe2x80x9cManipulation and Flow of Biological Fluids in Straight Channels Micromachined in Silicon,xe2x80x9d Clin. Chem. 40:43-47 disclose microfilters useful for separating blood cells from plasma etched into silicon wafers using a photolithographic process. These filter designs do not allow tangential or crossflow of the feed material past the barrier, which may be a narrower channel or barrier posts, to clear the barrier of particles. Further, in all cases, pressure must be applied to the system to obtain analyzable quantities of plasma. Because the minimum dimension of these filters is determined by a photolithographic process, they have a limit of about 1 micron. The photolithographic process is more sensitive to defects and requires tighter constraints on manufacturing than a process that relies on etching time to define the size of the channels as is used herein.
Wilding, P., et al. U.S. Pat. No. 5,304,487 issued Apr. 19, 1994 discloses mesoscale analytical devices for fluid handling comprising flow channels and fluid handling regions micromachined into silicon wafers. Again, no microfilters having tangential flow capabilities to aid in keeping the barrier free of particles are disclosed.
Raehse, W., et al. U.S. Pat. No. 4,751,003 issued Jun. 14, 1988 discloses a microfilter using a crossflow principle having polysulfone tubes with micropore diameters of 0.3 to 0.5 microns disposed in a cylindrical configuration. Ehrfeld, W. et al. U.S. Pat. No. 4,797,211 issued Jan. 31, 1989 discloses a crossflow microfilter comprising a microporous membrane having slit-shaped cross-sections. Solomon, H., et al. U.S. Pat. No. 4,212,742 issued Jul. 15, 1980 discloses a filtration apparatus for separating blood cells from liquids utilizing crossflow principles comprising multiple layers and membrane filters.
Ehrsam, C. et al. U.S. Pat. No. 4,801,379 issued Jan. 10, 1989 discloses a microfilter made of a foil having pores set into protuberances on the foil to aid in prevention of clogging. Hillman, R. U.S. Pat. No. 4,753,776 issued Jun. 28, 1988 discloses a microfilter useful for separating plasma from red blood cells comprising glass fibers using capillary action to promote flow.
Shoji, S. and Esashi, M. (1994), xe2x80x9cMicroflow devices and systems,xe2x80x9d J. Micromechanics and Microengineering 4:157-171, provide a general review of microvalves, micropumps, microflow sensors and integrated flow systems.
None of the foregoing references disclose or suggest the microfilter design disclosed herein which provides for tangential flow, ease and control of manufacturing, and minimization of surface tension problems.
All patents and publications referenced herein are incorporated by reference herein in their entirety.
This invention provides a microfilter useful for treating a feed liquid to separate liquid from particles contained therein comprising the following elements:
a) a feed inlet;
b) a feed exit;
c) a feed flow channel having a minimum dimension sufficient to permit flow of the particles and liquid therethrough, disposed between and in fluid communication with the feed inlet and the feed exit;
d) a filtrate collection channel parallel to the feed flow channel;
e) a barrier channel parallel to, between, and in fluid communication with the feed flow channel and the filtrate collection channel; the barrier channel having a minimum dimension sufficiently small to permit flow of the liquid but not the particles therethrough;
f) a filtrate exit in fluid communication with the filtrate collection channel;
wherein the elements are formed into the surface of a horizontal substrate; and
wherein the surface of the horizontal substrate is covered by a lid.
Preferably the microfilter also comprises a filtrate outlet channel connecting the filtrate collection channel and the filtrate exit.
Methods for making and using the microfilters of this invention are also provided.